Signals, receptors and escape: a functional genomics view of NK cell tumor cytotoxicity

Abstract

Natural killer (NK) cells are innate immune lymphocytes that play a fundamental role in cancer immunosurveillance owing to their inherent ability to recognize and eliminate tumor cells. A deeper understanding of the mechanisms regulating interactions between NK cells and malignant cells, which determine whether NK cells become activated, is important for the development of NK cell-based therapies. These studies employed genome-wide CRISPR screens to identify genes that either facilitate NK cell killing or promote tumor cell escape. In Paper I, loss of the flippase TMEM30A was identified as a resistance mechanism to NK cell killing. Gene depletion led to phosphatidylserine exposure that engaged TIM-3 and inhibited NK cells. In Paper II, BAP1 was shown to modulate IFN-γ responses in myeloid leukemia, particularly in ASXL1-mutated variants, and to limit NK cell activity by maintaining HLA class I expression. In Paper III, a CRISPR screen designed to identify potential ligands for the activating receptor NKp46, uncovered death receptors as key structures. Further experiments revealed that NKp46 interacts with TRAIL on the NK cell membrane, forming an immunoreceptor complex that triggers NK cell activation against malignant cells expressing death receptors. Finally, in Paper IV, an intact UFMylation pathway was found to be crucial for death receptor expression. Modulation of this pathway enhanced death receptor expression on cancer cells, thereby promoting NK cell activation. Taken together, these studies deepen our understanding of molecular mechanisms regulating NK cell interaction with malignant cells and identify new potential targets to improve NK cell-based immunotherapies.